Obesity and diabetic conditions are complex multifactorial disorders that affect approximately 50% of the U.S. adult population. Obesity is a known risk factor for diabetes mellitus, heart disease, hypertension, and even some forms of cancer. Overnutrition precipitates hyperinsulinemia, which promotes the storage of fat. The principal hormonal mediator of enteric insulin release in response to oral glucose is glucose-dependent insulinotropic polypeptide (GIP). We hypothesize that in addition to stimulating insulin release; GIP may function physiologically to directly enhance lipid deposition. Our hypothesis is further supported by Miyawaki et al, who recently demonstrated that mice deficient in the GIP receptor (GIPR) were protected from gaining weight when fed a high-fat diet compared to wild-type littermates. This observation suggests that inhibition of GIP signaling may prevent obesity. This grant proposal will 1) determine the role of GIP in the process of fat cell differentiation, and 2) identify downstream effectors of GIP signaling in adipocytes. By critically understanding GIP/GIPR signaling, our long-term objective is to antagonize GIP/GIPR and thereby prevent obesity and diabetes mellitus.